A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction

BACKGROUND: In previous studies, etanercept significantly improved plaque psoriasis and was well tolerated. OBJECTIVES: To examine further the efficacy and safety of etanercept and to assess maintenance of treatment effect after dose reduction of etanercept. METHODS: In this multicentre 24-week study in the U.S.A., Canada and Western Europe, patients were at least 18 years old; had active, clinically stable plaque psoriasis involving at least 10% of body surface area; had a minimum Psoriasis Area and Severity Index (PASI) of 10 at screening; and had received or were a candidate to receive systemic psoriasis therapy or phototherapy. During the first 12 weeks of the study, patients were randomly assigned to receive by subcutaneous injection etanercept twice weekly (BIW) at a dose of 50 mg or 25 mg, or placebo BIW in a double-blind fashion. During the second 12 weeks, all patients received etanercept 25 mg BIW. The primary endpoint was a 75% or greater improvement from baseline in PASI (PASI 75) at 12 weeks. RESULTS: Five hundred and eighty-three subjects were randomized and received at least one dose of study drug. At week 12, a PASI 75 was achieved by 49% of patients in the etanercept 50 mg BIW group, 34% in the 25 mg BIW group, and 3% in the placebo group (P < 0.0001 for each etanercept group compared with placebo). At week 24 (after 12 weeks of open-label 25 mg etanercept BIW), a PASI 75 was achieved by 54% of patients whose dose was reduced from 50 mg BIW to 25 mg BIW, by 45% of patients in the continuous 25 mg BIW group, and by 28% in the group that received placebo followed by etanercept 25 mg BIW. Etanercept was well tolerated throughout the study. CONCLUSIONS: Etanercept provided clinically meaningful benefit to patients with chronic plaque psoriasis, with no apparent decrease in efficacy after dose reduction.     

Once weekly administration of etanercept 50 mg is efficacious and well tolerated in patients with moderate-to-severe plaque psoriasis: a randomized controlled trial with open-label extension

Background In previous studies, etanercept 25 mg twice weekly (BIW) or 50 mg BIW significantly reduced disease severity in patients with plaque psoriasis and demonstrated a favourable safety profile. Objectives To assess the efficacy and safety of etanercept 50 mg administered once weekly (QW) compared with placebo in patients with moderate‐to‐severe plaque psoriasis over 24 weeks. Methods This study was conducted in two parts: (i) a 12‐week, double‐blind, placebo‐controlled phase, in which patients received etanercept 50 mg QW or placebo QW; and (ii) a 12‐week, open‐label extension phase, in which all patients received etanercept 50 mg QW. Primary endpoint was a 75% or greater improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) at week 12. Secondary endpoints included percentage PASI improvement and Physician’s Global Assessment (PGA). Results One hundred and forty‐two patients were analysed in the double‐blind phase; 126 patients entered the open‐label phase. At week 12, significantly more patients receiving etanercept 50 mg QW (37·5%) achieved PASI 75 response than patients receiving placebo (2·2%; P < 0·0001). At week 24, 71·1% in the etanercept–etanercept group and 44·4% in the placebo–etanercept group achieved PASI 75. Mean percentage of PASI improvement from baseline was 55·4% with etanercept vs. 9·4% worsening with placebo at week 12 (P < 0·0001), with 77·4% and 57·7% improvement in the etanercept–etanercept and placebo–etanercept groups at week 24. A PGA score of 0–1 (clear–almost clear) was achieved by 64% and 42% in the etanercept–etanercept and placebo–etanercept groups at week 24, respectively. Etanercept 50 mg QW was well tolerated. No deaths, serious infections, opportunistic infections (including tuberculosis), demyelinating disorders, malignancies or new safety signals were reported. Conclusions Nearly three‐quarters of patients with moderate‐to‐severe psoriasis receiving etanercept 50 mg QW achieved significant improvement in disease severity over 24 weeks. This study also showed a favourable tolerability and safety profile with etanercept 50 mg QW.     

Impact of adalimumab treatment on health-related quality of life and other patient-reported outcomes: results from a 16-week randomized controlled trial in patients with moderate to severe plaque psoriasis

BACKGROUND: Health-related quality of life (HRQOL) and other patient-reported outcomes (PROs) are important in evaluating the impact of psoriasis and its treatment. OBJECTIVES: To assess the impact of adalimumab treatment on HRQOL and other PROs in patients with moderate to severe psoriasis. METHODS: A 16-week, double-blind, double-dummy, randomized controlled trial evaluated the efficacy and safety of adalimumab in 271 adults with moderate to severe chronic plaque psoriasis. Patients were randomized in a 2:2:1 ratio to adalimumab, methotrexate (MTX) or placebo. PROs were evaluated throughout the study and included the Dermatology Life Quality Index (DLQI), Patient's Global Assessment of disease severity, plaque psoriasis and psoriatic arthritis pain visual analogue scale (VAS), Psoriasis-Related Pruritus Assessment and EuroQOL 5D (EQ-5D). RESULTS: Statistically significant differences were observed between the adalimumab- and placebo-treated and the MTX-treated groups on mean DLQI total scores during the 16-week double-blind study (both P<0.001). Significant differences, favouring adalimumab compared with placebo, were also observed on the Patient's Global Assessment of disease severity (P<0.001), VAS for pain (P<0.001), Psoriasis-Related Pruritus Assessment (P<0.001), EQ-5D VAS (P<0.001) and EQ-5D index score (P<0.01). Compared with MTX, adalimumab resulted in statistically significantly greater improvements in the Patient's Global Assessment of disease severity (P<0.001), the VAS for pain (P<0.01) and the Psoriasis-Related Pruritus Assessment (P<0.001). CONCLUSIONS: Adalimumab was efficacious in improving dermatology-specific HRQOL, disease control and symptom outcomes in patients with moderate to severe psoriasis.     

Improvement in quality of life with infliximab induction and maintenance therapy in patients with moderate-to-severe psoriasis: a randomized controlled trial

BACKGROUND: Psoriasis has a well-documented, markedly negative effect on patient quality of life. OBJECTIVES: To evaluate the impact of long-term infliximab maintenance therapy on health-related quality of life (HRQoL) in patients with psoriasis. METHODS: The Dermatology Life Quality Index (DLQI) and 36-item Short Form Health Survey (SF-36) were administered as part of the pivotal double-blind, placebo-controlled efficacy and safety EXPRESS study of infliximab in chronic plaque psoriasis. In total, 378 patients with moderate-to-severe psoriasis were enrolled at 32 centres in Europe and Canada. Patients were randomized to receive either placebo or infliximab 5 mg kg(-1) induction at weeks 0, 2 and 6 followed by maintenance every 8 weeks; placebo patients crossed over at week 24 to receive the infliximab induction and maintenance regimen. RESULTS: At week 10, infliximab-treated patients had significantly greater improvement in DLQI scores (P < 0.001) and SF-36 physical and mental component summary scores (P < 0.001) than placebo-treated patients. Significant improvement (P < 0.001) was also seen in all eight SF-36 subscales, and was greatest for the "Bodily Pain" and "Social Functioning" scales. Significant improvement in HRQoL persisted with maintenance infliximab treatment at week 24 (P < 0.001), with patients achieving a Psoriasis Area and Severity Index score of 0 reporting the greatest benefit. Treatment-related HRQoL improvement remained substantial at week 50. CONCLUSIONS: Infliximab induction and maintenance regimens resulted in rapid, substantial, sustained and clinically meaningful improvement in both dermatology-specific and general quality of life indices in patients with psoriasis, with total clearance resulting in maximum improvement.     

Combination of skin,joint and quality of life outcomes with etanercept in psoriasis and psoriatic arthritis in the PRESTA trial

Background Psoriasis and psoriatic arthritis (PsA) affect skin, and/or joints and quality of life (QoL). Objective To better assess the success in multiple attributes in subjects with both active psoriasis and PsA, the objective was to quantify the proportion of those who achieved substantial improvement in a composite measure of skin symptoms, joint manifestations, and QoL, on one of two treatment regimens. Methods Subjects (n = 752) with psoriasis and PsA (mean age: 46.5 years, 62.9% male) received etanercept (ETN) 50 mg twice weekly (BIW; n = 379) or 50 mg weekly (QW; n = 373) for 12 weeks, followed by open‐label ETN 50 mg QW for 12 weeks. Skin and joint symptoms and QoL were assessed using psoriasis area and severity index (PASI), American College of Rheumatology criteria (ACR) and Euro‐QoL (EQ‐5D), respectively. Results By week 24, 30.6% and 25.8% of subjects receiving ETN 50 mg BIW/QW and ETN 50 mg QW/QW, respectively (P = 0.198) achieved the composite measure of efficacy for skin plus joints plus QoL (PASI 75 + ACR 50 + EQ‐5D VAS >82). Conclusion At 24 weeks, 25.8–30.6% met the triad of rigorous efficacy outcomes. Evaluation of treatment efficacy should address the multiple components of this disease complex; therefore it may be important to consider this composite measure in future trials.     

A comparison of twice-daily calcipotriol ointment with once-daily short-contact dithranol cream therapy: quality-of-life outcomes of a randomized controlled trial of supervised treatment of psoriasis in a day-care setting

BACKGROUND: Calcipotriol ointment and short-contact dithranol cream therapy are well-established topical treatments for psoriasis. Quality of life, i.e. the physical, psychological, and social functioning and well-being of the patient, has become an essential outcome measure in chronic skin disease. OBJECTIVES: To compare the quality-of-life outcomes of calcipotriol ointment with that of short-contact dithranol cream in a supervised treatment regimen, and to determine the degree of improvement in quality of life these topical treatments can accomplish. METHODS: In a multicentre randomized controlled trial in six centres in the Netherlands, 106 patients with chronic plaque psoriasis were included, 54 receiving calcipotriol ointment twice daily and 52 dithranol cream once daily in a 12-week intensive treatment programme. Patients were treated at the day-care centre, using the care instruction principle of daily visits during the first week and twice-weekly visits subsequently for up to 12 weeks. Quality of life was assessed with the Skindex-29 and the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36). RESULTS: At the end of treatment, no statistically significant differences were found between the calcipotriol and the dithranol group in any of the quality-of-life domains or scales of the Skindex-29 and the SF-36. Over time, a significant improvement of quality of life was found on all three scales of the dermatology-specific Skindex-29, predominantly of a moderate magnitude. In the calcipotriol group, a significant change of a small magnitude was found in the Physical Component Summary of the SF-36. No significant changes were found in the Mental Component Summary (or on any of the eight scales composing the questionnaire) of the SF-36. CONCLUSIONS: The hypothesis was confirmed, that no statistically significant differences in improvement of quality of life could be found between calcipotriol ointment and dithranol short-contact cream in a day-care setting. Given this result, both calcipotriol and dithranol can be welcome alternatives for the patient. Calcipotriol, being more practical and patient friendly, can be considered as a first-line approach in clinical practice. However, in patients recalcitrant to calcipotriol and/or other topical treatments, preference should be given to the dithranol regimen. Topical treatment in combination with interventions explicitly focusing on improvement of coping behaviour and psychosocial functioning may further increase the degree of improvement in the psychosocial domains of quality of life. The results of this study are likely to give further evidence to the notion that the generic SF-36 is little or not responsive to small to moderate changes in quality of life in mild to moderate psoriasis.     

Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION)

BACKGROUND: Biologic therapies such as adalimumab, a tumour necrosis factor antagonist, are safe and effective in the treatment of moderate to severe chronic plaque psoriasis. OBJECTIVES: To compare a biologic agent with methotrexate, a traditional systemic agent, to define clearly the role of biologics in psoriasis. METHODS: Patients with moderate to severe plaque psoriasis were randomized to adalimumab (80 mg subcutaneously at week 0, then 40 mg every other week, n=108), methotrexate (7.5 mg orally, increased as needed and as tolerated to 25 mg weekly; n=110) or placebo (n=53) for 16 weeks. The primary efficacy endpoint was the proportion of patients achieving at least a 75% improvement in the Psoriasis Area and Severity Index (PASI 75) after 16 weeks. Safety was assessed at all visits through week 16. RESULTS: After 16 weeks, 79.6% of adalimumab-treated patients achieved PASI 75, compared with 35.5% for methotrexate (P<0.001 vs. adalimumab) and 18.9% for placebo (P<0.001 vs. adalimumab). Statistically significantly more adalimumab-treated patients (16.7%) than methotrexate-treated patients (7.3%) or placebo-treated patients (1.9%) achieved complete clearance of disease. The response to adalimumab was rapid, with a 57% improvement in mean PASI observed at week 4. Adverse events were similar across treatment groups. Adverse events leading to study discontinuation were greatest in the methotrexate group, primarily because of hepatic-related adverse events. CONCLUSIONS: After 16 weeks, adalimumab demonstrated significantly superior efficacy and more rapid improvements in psoriasis compared with either methotrexate or placebo.     

Treatment of erythrodermic psoriasis with etanercept

BACKGROUND: Severe variants of psoriasis, such as erythrodermic psoriasis, may be associated with serious morbidity and mortality. Current treatment options for erythrodermic psoriasis are limited, unsatisfactory and potentially associated with organ-specific toxicity. Recently, a new class of agents, targeted biological therapies, has emerged. Etanercept is a recombinant human fusion protein acting as a competitive inhibitor of tumour necrosis factor-alpha. The safety and efficacy of etanercept have been widely demonstrated in psoriatic arthritis and moderate to severe plaque-type psoriasis. OBJECTIVES: To assess the efficacy and tolerability of etanercept in the treatment of erythrodermic psoriasis over a period of 24 weeks. METHODS: Ten patients, eight men and two women, were selected to receive etanercept 25 mg subcutaneously twice weekly. The Psoriasis Area and Severity Index (PASI) score, ranging from 0 to 72, was used to assess the severity of disease. RESULTS: Etanercept was well tolerated and led to a significant reduction in the severity of disease over the period of treatment. After 24 weeks, the mean PASI score decreased from 39.1 (baseline) to 5.1. At week 12, five of 10 (50%) patients achieved an improvement of PASI score from baseline exceeding 75%. At week 24, six of 10 patients (60%) achieved or maintained an improvement of PASI score from baseline exceeding 75% while two patients (20%) maintained an improvement of between 50% and 75%. CONCLUSIONS: In this study, etanercept has been demonstrated to be an effective treatment for erythrodermic psoriasis, providing a safe and convenient alternative to current therapies.     

Two years of experience with etanercept in recalcitrant psoriasis

BACKGROUND: The safety and efficacy of etanercept have been demonstrated in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Placebo-controlled trials have indicated the efficacy of etanercept in moderate to severe psoriasis. OBJECTIVES: To observe the efficacy and safety profile of etanercept in patients with severe psoriasis resistant to other systemic agents over a 2-year period. METHODS: In this retrospective study, 49 patients were treated with etanercept between March 2004 and March 2006. All patients were screened for tuberculosis with tuberculin test and a chest X-ray. Thirty-nine patients started on etanercept 25 mg twice weekly (BIW) and 10 started at 50 mg BIW when judged to be clinically indicated. In 19 of those on 25 mg BIW, the dose was increased to 50 mg BIW because of poor response and psoriasis flaring. Response to treatment was assessed by Psoriasis Area and Severity Index (PASI) and static Physician Global Assessment (PGA). Patients were reviewed at 8-week intervals, when clinical response and adverse effects were noted. RESULTS: Forty-four patients (90%) had chronic plaque psoriasis, two (4%) were suberythrodermic, one (2%) had palmoplantar pustular psoriasis and two (4%) had acrodermatitis continua of Hallopeau. At least 75% reduction in PASI was achieved in 47% of patients at week 24 and 66% at week 48. At week 24, 44% had a PGA score of excellent, and at week 48, 58% scored excellent. In 12 who cleared, etanercept was stopped. Ten of these relapsed and etanercept was recommenced, while two remained in remission (mean 12.5 weeks). One patient developed extrapulmonary tuberculosis. CONCLUSIONS: Etanercept was effective in severe psoriasis recalcitrant to other systemic medication. The drug was well tolerated. Development of tuberculosis in one patient underlines the need for rigorous tuberculosis screening.     

Leflunomide in the treatment of psoriasis: results of a phase II open trial

BACKGROUND: Psoriasis is recognized as the most prevalent T-cell-mediated inflammatory disease in humans, with predominantly activated T-helper (Th) 1 cell effectors. Leflunomide exerts its anti-inflammatory activities by preventing the generation of proinflammatory Th1 effectors and promoting Th2 cell differentiation. OBJECTIVES: To determine the safety and efficacy of leflunomide in patients with moderate to severe plaque-type psoriasis. METHODS: In an open-label phase II trial, eight patients with psoriasis received oral leflunomide 20 mg daily for 12 weeks. Patients were evaluated for improvement in psoriasis, quality of life, histological changes and toxicity. RESULTS: Antipsoriatic effects were obtained in all but two patients. A significant decrease was observed in the mean +/- SD Psoriasis Area and Severity Index score, from 20.08 +/- 6.85 before treatment to 12.51 +/- 11.83 after (P = 0.03). The antipsoriatic efficiency was confirmed histologically, with a significant mean +/- SD decrease in epidermal thickness, from 0.73 +/- 0.19 micro m before to 0.31 +/- 0.16 microm after (P = 0.01). The quality of life score showed an improvement, from 8.58 +/- 2.38 (mean +/- SD) before to 5.33 +/- 1.95 after (P = 0.02). The treatment was well tolerated; adverse reactions primarily consisted of transitory gastrointestinal events. CONCLUSIONS: Our data suggest that leflunomide for plaque-type psoriasis is a safe and clinically effective option as monotherapy. However, double-blind, placebo-controlled studies are needed.     

Treatment of psoriasis with topical sirolimus: preclinical development and a randomized, double-blind trial

BACKGROUND: Systemically administered sirolimus has demonstrated efficacy in psoriasis in a multicentre European study. OBJECTIVES: To determine the efficacy and safety of topically applied sirolimus in treating psoriasis. METHODS: In vitro studies were followed by a pilot study designed to determine if sirolimus penetrates human skin, and by a randomized, double-blind, left-right comparative, dose-ranging study consisting of treatment with 2.2% sirolimus for 6 weeks and 8% sirolimus for an additional 6 weeks in 24 patients with stable, chronic plaque psoriasis. The primary outcome measure was clinical score. Secondary measures were ultrasound plaque thickness, plaque erythema, and computerized image analysis of immunohistochemical stains for immunocytes and proliferating cells. Pharmacokinetics and blood chemistry monitoring for safety were also performed. RESULTS: A significant reduction in the clinical score (P = 0.03) (mean score 9.1 following sirolimus vs. 11.2 in control) was achieved with topical sirolimus. Measurements of plaque thickness and erythema did not show significant improvement with treatment. Computerized image analysis of biopsies showed a significant reduction in CD4+ cells (P = 0.0054) and proliferating cells (stained by Ki-67) in the epidermis (P = 0.0153) with sirolimus treatment compared with control. CONCLUSIONS: Topically applied sirolimus penetrates normal skin and may have some antipsoriatic and immunosuppressive activity.     

The effect of inositol supplements on the psoriasis of patients taking lithium: a randomized, placebo-controlled trial

BACKGROUND: Lithium carbonate is the most widely used long-term treatment for bipolar affective disorders, but its ability to trigger and exacerbate psoriasis can become a major problem in patients for whom lithium is the only treatment option. Inositol depletion underlies the action of lithium in bipolar affective disorders and there are good theoretical reasons why the use of inositol supplements might be expected to help this group of patients. OBJECTIVES: To determine whether inositol supplements improve the psoriasis of patients on lithium therapy. METHODS: Fifteen patients with psoriasis, who were taking lithium, took part in a randomized, double-blind, placebo-controlled, crossover clinical trial comparing the effect of inositol supplements with those of a placebo (lactose). Changes in the severity of their psoriasis were measured by Psoriasis Area and Severity Index scores recorded before and after the different courses of treatment. The effect of inositol supplements on the psoriasis of 11 patients who were not taking lithium was evaluated in the same way. RESULTS: The inositol supplements had a significantly beneficial effect on the psoriasis of patients taking lithium. No such effect was detected on the psoriasis of patients not on lithium. CONCLUSIONS: The use of inositol supplements is worth considering for patients with intractable psoriasis who need to continue to take lithium for bipolar affective disorders.     

The impact of a two-compound product containing calcipotriol and betamethasone dipropionate (Daivobet/ Dovobet) on the quality of life in patients with psoriasis vulgaris: a randomized controlled trial

BACKGROUND: Psoriasis is a common disease and may have a significant impact on patients' quality of life (QoL). OBJECTIVES: To assess the impact on QoL of a new two-compound product (TCP) (Daivobet/Dovobet; LEO Pharma) which combines the topical vitamin D analogue calcipotriol (50 microg g(-1)) and the World Health Organization group III corticosteroid betamethasone dipropionate (0.5 mg g(-1)) in a single ointment vs. calcipotriol monotherapy using a placebo-controlled study design. METHODS: The Psoriasis Disability Index and the EuroQoL 5D questionnaire and visual analogue scale (VAS) were used in this study, which enrolled 828 patients with psoriasis vulgaris for treatment lasting up to 4 weeks. These QoL instruments were completed by patients before and after treatment with the TCP of calcipotriol and betamethasone dipropionate used once or twice daily, calcipotriol alone twice daily and vehicle twice daily. RESULTS: The TCP used once or twice daily and calcipotriol used twice daily were found to have statistically significant beneficial effects on patients' QoL over the course of treatment, and each was demonstrated to have a statistically significant benefit on QoL over vehicle. The TCP, applied once daily, was superior to calcipotriol twice daily in terms of reductions on the EuroQoL 5D questionnaire and VAS. CONCLUSIONS: The results suggest that calcipotriol twice daily and the new TCP applied twice daily have a substantial effect on QoL. Once-daily application of the TCP is superior to calcipotriol twice daily terms of QoL, which reflects the superior efficacy of this combination and the advantage of once-daily application when compared with twice-daily application.     

Infliximab treatment results in significant improvement in the quality of life of patients with severe psoriasis: a double-blind placebo-controlled trial

Background Psoriasis is a chronic disease that significantly diminishes the health‐related quality of life (HRQOL). Infliximab is a chimeric, tumour necrosis factor α monoclonal antibody that has been shown to improve the signs and symptoms of plaque psoriasis. Objectives The objective of this study was to evaluate the effect of infliximab induction therapy on the HRQOL of patients with severe plaque psoriasis. Methods In this double‐blind, placebo‐controlled trial, 249 patients were randomly assigned to receive intravenous infusions of 3 or 5 mg kg^?1 of infliximab or placebo and were treated at weeks 0, 2 and 6. Patients completed the Dermatology Life Quality Index (DLQI) at baseline and week 10. Results Infliximab induction therapy resulted in a substantial improvement in HRQOL. At week 10, patients in the infliximab 3‐ and 5‐mg kg^?1 groups showed a median percentage improvement in DLQI scores of 84·0% and 91·0%, respectively, compared with 0% in the placebo group (P < 0·001). The median decrease from baseline in DLQI score at week 10 was 8·0 and 10·0 for the 3 and 5 mg kg^?1 infliximab groups, respectively, compared with 0 in the placebo group (P < 0·001). Thirty‐three per cent and 40% of patients in the 3 and 5 mg kg^?1 infliximab groups, respectively, had a DLQI score of 0 at week 10, compared with 2% in the placebo group (P < 0·001). There was a strong correlation between the percentage change from baseline at week 10 in Psoriasis Area and Severity Index (PASI) scores and the percentage change in DLQI scores during the same period (Spearman's correlation, 0·61, P < 0·001). When the infliximab and placebo treatment groups were combined, patients with at least 75% improvement in PASI scores between baseline and week 10 had a greater mean improvement in DLQI scores (81%) than those with 50–75% improvement in PASI during the same period (60%). Conclusions Infliximab induction therapy resulted in significant improvement in HRQOL in patients with severe psoriasis.     

Initial experience with routine administration of etanercept in psoriasis

BACKGROUND: Etanercept and efalizumab recently became available and reimbursed for routine use in severe psoriasis in the Netherlands. The criteria for reimbursement are Psoriasis Area and Severity Index (PASI) > or = 10 (or Skindex-29 > or = 35 if PASI > or = 8 and < 10) and ineffectiveness of ultraviolet (UV) B/psoralen plus UVA, methotrexate and ciclosporin, or a contraindication to or serious side-effect(s) during these treatments. OBJECTIVES: We hypothesized: (i) that efficacy would be lower than that obtained in published phase II and III studies because (a) resistance to all conventional therapies as a reimbursement condition would select for more resistant cases and (b) inclusion would be more restricted to severe cases (higher PASI), and (ii) that efficacy would be lower in obese patients due to the possible role of adipose tissue in tumour necrosis factor (TNF)-alpha homeostasis. METHODS: We treated 50 patients (38 men, 12 women; mean PASI 15.8) with etanercept 25 mg or 50 mg twice weekly and evaluated in a retrospective analysis the efficacy and safety in comparison with data from published trials. Additionally, we related the clinical effect to the body mass index (BMI), for adipose tissue is thought to have a possible role in TNF-alpha homeostasis. RESULTS: Based on the literature, 30% and 49% of the patients treated with etanercept 25 mg and 50 mg twice weekly, respectively, should have achieved 75% or more improvement in PASI compared with baseline (PASI 75), and 10% and 21%, respectively, should have achieved 90% or more improvement (PASI 90). Our data showed that 21% in the 2 x 25 mg group and 23% in the 2 x 50 mg group achieved PASI 75. PASI 90 was only attained in 7% of patients treated with 2 x 25 mg and 6% of those treated with 2 x 50 mg. Contrary to our hypothesis, the mean initial PASI was comparable with the mean PASI mentioned in the phase II and III clinical trials. Although fatigue is not identified as a side-effect of etanercept, 10% of our patients reported fatigue as an adverse event during etanercept treatment. High BMI, indicating overweight or obesity, was found both in patients with little efficacy and in patients achieving PASI 75 or better. CONCLUSIONS: Use of etanercept in real practice gives impressive results, but these are generally less favourable than those published in clinical trial reports. This is probably due to the stringent conditions for reimbursement, which select for more treatment-resistant patients. Fatigue as a possible side-effect of etanercept should also be an issue for further investigation. Finally, the BMI does not seem to influence the patients' response to etanercept, although further investigations would be needed to confirm this.     

Terbinafine in fungal infections of the nails: a meta-analysis of randomized clinical trials

BACKGROUND: The antitumour necrosis factor (TNF) activity of etanercept has been utilized to generate an important and novel treatment for rheumatoid arthritis. TNF has also been implicated in the pathogenesis of psoriasis. OBJECTIVES: To determine whether blockade of TNF activity by etanercept may provide an additional treatment option for patients with psoriasis. METHODS: In an uncontrolled trial, etanercept was added to the treatment regimen in six patients with severe recalcitrant psoriasis (three also with psoriatic arthritis) partially resistant to other ongoing systemic agents. RESULTS: In each case, the disease activity showed marked improvement on addition of etanercept therapy. No added toxicity was found with etanercept. CONCLUSIONS: Etanercept appears to be a promising immunomodulatory agent that can be used in combination therapy for the treatment of psoriasis, and a prospective controlled trial may be warranted.     

Efficacy of sirolimus (rapamycin) administered concomitantly with a subtherapeutic dose of cyclosporin in the treatment of severe psoriasis: a randomized controlled trial

BACKGROUND: The identification of a highly potent immunosuppressive/antiproliferative agent with an acceptable toxicity profile has long been a goal for the management of severe plaque psoriasis. OBJECTIVES: To investigate the efficacy and safety of sirolimus (Rapamune) for severe psoriasis when given alone or in association with cyclosporin. METHODS: In a randomized, double-blind, eight parallel group, pilot study in 24 out-patient centres in seven European countries, 150 patients, 18 years and older, with severe chronic plaque psoriasis were given sirolimus 0.5, 1.5 and 3.0 mg m(-2) daily for 8 weeks, either alone or in association with a subtherapeutic dose of cyclosporin (1.25 mg kg(-1) daily). Cyclosporin 5 mg kg(-1) daily was the positive control and cyclosporin 1.25 mg kg(-1) daily the negative control. The primary efficacy variable was the mean percentage reduction in Psoriasis Area and Severity Index (PASI). Safety assessments included monitoring of adverse events, clinical laboratory parameters and sirolimus/cyclosporin blood concentrations. RESULTS: The greatest mean percentage decreases in PASI were seen with cyclosporin 5.0 mg kg(-1) daily (70.5%) and with sirolimus 3.0 mg m(-2) daily + cyclosporin 1.25 mg kg(-1) daily (63.7%). Both groups demonstrated significantly better results than cyclosporin 1.25 mg kg(-1) daily (mean decrease 33.4%). Serum creatinine levels were significantly lower for groups with sirolimus alone and sirolimus plus reduced-dose cyclosporin when compared with cyclosporin 5.0 mg kg(-1) daily. Adverse events associated with sirolimus included thrombocytopenia (5%), hyperlipidaemia (9%), aphthous stomatitis (9%) and acne (13%), whereas adverse events associated with cyclosporin included hot flushes (12%), hyperlipidaemia (9%) and increased serum creatinine (9%). CONCLUSIONS: The concomitant administration of sirolimus with a subtherapeutic dose of cyclosporin in severe psoriasis may permit a reduction in their respective toxicities, notably cyclosporin-induced nephrotoxicity.     

Combining etanercept and acitretin in the therapy of chronic plaque psoriasis: a 24-week, randomized, controlled, investigator-blinded pilot trial

Background Combination treatments may increase efficacy while reducing dosages and side‐effects of individual agents. No randomized controlled trials have been published combining biologics with conventional agents for psoriasis. Objectives To investigate the efficacy and safety of the association of acitretin and etanercept in the treatment of moderate to severe chronic plaque psoriasis. Methods A 24‐week, randomized, controlled, investigator‐blinded pilot trial was conducted. Sixty adult patients with moderate to severe chronic plaque psoriasis were randomized into three groups to receive etanercept 25 mg twice weekly subcutaneously, oral acitretin 0·4 mg kg^?1 daily or etanercept 25 mg once weekly plus acitretin 0·4 mg kg^?1 daily. The primary end point was a 75% or greater improvement in Psoriasis Area and Severity Index (PASI) from baseline (PASI 75) at week 24. Results At week 24, PASI 75 response was achieved by 10 of 22 patients in the etanercept group (45%), six of 20 in the acitretin group (30%) and eight of 18 (44%) in the group treated with etanercept plus acitretin (P = 0·001 for both etanercept groups compared with acitretin alone). A 50% or greater improvement from baseline in PASI was achieved by 15 of 22 (68%), 10 of 20 (50%) and 12 of 18 (67%) patients, respectively (P = 0·001). The safety profiles of the three groups were similar. Conclusions A combined therapeutic regimen with etanercept 25 mg once weekly and acitretin 0·4 mg kg^?1 daily is as effective as etanercept 25 mg twice weekly, and more effective than acitretin alone. Although larger studies are needed to confirm these results, the etanercept/acitretin association could offer several advantages in the therapy of moderate to severe chronic plaque psoriasis.     

A comparison of twice-daily calcipotriol ointment with once-daily short-contact dithranol cream therapy: a randomized controlled trial of supervised treatment of psoriasis vulgaris in a day-care setting

BACKGROUND: Calcipotriol has become a first-line treatment for psoriasis. Its efficacy and safety have been shown in many comparative clinical trials carried out in outpatients. In a comparative study in patients visiting the outpatient department once every 14 days, it was shown that calcipotriol was more effective and better tolerated compared with dithranol. OBJECTIVES: To compare the clinical efficacy of calcipotriol ointment with that of dithranol cream in a supervised treatment regimen. METHODS: In a multicentre randomized controlled trial in six centres in the Netherlands, 106 patients with chronic plaque psoriasis were included, 54 receiving calcipotriol ointment twice daily and 52 dithranol cream once daily. Patients were treated at the day-care centre, using the care instruction principle of daily visits during the first week and twice-weekly visits subsequently for up to 12 weeks. RESULTS: This study failed to prove that calcipotriol is as efficacious as dithranol when used in a day-care setting (noninferiority test). The mean percentage reduction in Psoriasis Area and Severity Index from baseline to end of treatment was 57.0% in the calcipotriol group vs. 63.6% in the dithranol group. However, the two-sided test for superiority indicated no statistically significant difference between the treatment groups (P = 0.39). At the end of treatment, 15% of the patients treated with calcipotriol ointment and 25% of those treated with dithranol cream did not require any further treatment. Although calcipotriol ointment appeared to be more effective during the first 8 weeks, a difference was no longer apparent at 12 weeks. In comparison with the high number of drop-outs due to cutaneous side-effects in the calcipotriol group, the frequency of a tolerable degree of irritation appeared to be higher in patients treated with dithranol. However, concomitant corticosteroid treatment of dithranol irritation in seven patients may have contributed to this difference between both treatments. Moreover, patients receiving therapy with calcipotriol ointment experienced fewer application-related skin and subcutaneous tissue disorders than patients treated with dithranol cream: 21 of 53 (40%) and 37 of 52 (71%), respectively. This difference is statistically significant (P = 0.001). CONCLUSIONS: The hypothesis that calcipotriol ointment might be at least as effective as dithranol cream in the day-care setting could not be proven in the present study. Whereas calcipotriol has become a mainstay in the routine outpatient treatment of psoriasis not requiring a day-care setting, dithranol treatment, being difficult as a routine outpatient therapy, has increased efficacy and improved tolerability if the treatment is carried out in a day-care setting.